Compositions and methods for cancer immunotherapy

Abstract

Provided is a cancer therapeutic agent comprising a cancer targeting molecule linked to a liver-expressed chemokine (LEC). In one embodiment, the cancer targeting molecule is an antibody that targets cancer cells or tumors in vivo. The cancer targeting molecule is associated non-covalently or covalently with LEC. The cancer therapeutic agents of the invention are useful for the treatment of cancer in an individual by reducing the size of a tumor or inhibiting the growth of cancer cells in an individual and/or by inhibiting the development of metastasis. The effectiveness of the therapy using the LEC cancer therapeutic agents can be increased by reducing the activity of immunoregulatory T cells and/or by adoptively transferring immune T cells.

What is claimed is: 
     
       1. A method of reducing the size of a tumor or inhibiting the growth of cancer cells in an individual, consisting essentially of reducing the activity of immunoregulatory T cells in the individual and administering an effective amount of a cancer therapeutic agent comprising a cancer targeting molecule linked to a liver-expressed chemokine (LEC) to the individual wherein said cancer therapeutic agent can target to cancer cells or tumor in vivo and said LEC functions as a chemoattractant for monocytes, lymphocytes, or polymorphonuclear leukocytes. 
     
     
       2. A method according to  claim 1  wherein said reducing the activity of immunoregulatory T cells involves (a) removing ex vivo immunoregulatory T cells from the individual or (b) depleting or inactivating in vivo immunoregulatory T cells in the individual. 
     
     
       3. A method according to  claim 1  wherein said reducing the activity of immunoregulatory T cells is achieved using at least one antibody that binds to the immunoregulatory T cells. 
     
     
       4. A method according to  claim 3  wherein said at least one antibody is specific for the IL-2 receptor. 
     
     
       5. A method according to  claim 4  wherein said antibody specific for the IL-2 receptor is an antibody specific for CD25. 
     
     
       6. A method according to  claim 1  wherein said reducing the activity of immunoregulatory T cells is performed before administering said cancer therapeutic agent. 
     
     
       7. A method according to  claim 1  further comprising administering T cells which have cytotoxic activity against the cancer. 
     
     
       8. A method according to  claim 7  wherein said administering T cells comprises removing T cells from the individual, activating the T cells, and then administering the activated T cells to the individual. 
     
     
       9. A method according to  claim 1 , wherein said cancer targeting molecule is an antibody. 
     
     
       10. A method according to  claim 9  wherein said antibody is specific for a tumor cell-surface antigen. 
     
     
       11. A method according to  claim 9  wherein said antibody is specific for a stromal component of a tumor. 
     
     
       12. A method according to  claim 9  wherein said antibody is specific for an intracellular antigen. 
     
     
       13. A method according to  claim 12  wherein said antibody is specific for an intranuclear antigen. 
     
     
       14. A method according to  claim 13  wherein said antibody is a murine, chimeric, humanized, or human form of murine antibody TNT-1, TNT-2, TNT-3 or NHS76. 
     
     
       15. A method according to  claim 1  wherein said cancer targeting molecule and LEC are covalently linked. 
     
     
       16. A method according to  claim 1  wherein said cancer targeting molecule is a protein linked to LEC by genetic fusion. 
     
     
       17. A method according to  claim 16  wherein LEC is fused at its C-terminus to the N-terminus of said cancer targeting molecule. 
     
     
       18. A method according to  claim 17  wherein the cancer targeting molecule is an antibody and wherein LEC is fused to the N-terminus of the light or heavy chain of said antibody or wherein LEC is fused to the N-terminus of the light and the heavy chain of said antibody. 
     
     
       19. A method according to  claim 1  wherein said LEC has an amino acid sequence which has at least 95% sequence identity with SEQ ID NO: 3. 
     
     
       20. A method according to  claim 1  wherein said LEC has an amino acid sequence which has at least 98% sequence identity with SEQ ID NO: 3. 
     
     
       21. A method according to  claim 1  wherein said LEC has the amino acid sequence shown in SEQ ID NO: 3. 
     
     
       22. A method of reducing the size of a tumor or inhibiting the growth of cancer cells in an individual, wherein the activity of immunoregulatory T cells has been reduced in said individual, comprising reducing the activity of immunorequlatory T cells in the individual administering an effective amount of a cancer therapeutic agent comprising a cancer targeting molecule linked to a liver-expressed chemokine (LEC) to the individual wherein said cancer therapeutic agent can target to cancer cells or tumor in vivo and said LEC functions as a chemoattractant for monocytes, lymphocytes, or polymorphonuclear leukocytes. 
     
     
       23. A method according to  claim 22  wherein the activity of immunoregulatory T cells has been reduced by a method comprising (a) removing ex vivo immunoregulatory T cells from the individual or (b) depleting or inactivating in vivo immunoregulatory T cells in the individual. 
     
     
       24. A method according to  claim 22  wherein the activity of immunoregulatory T cells has been reduced by a method comprising using at least one antibody that binds to the immunoregulatory T cells. 
     
     
       25. A method according to  claim 24  wherein said at least one antibody is specific for the IL-2 receptor. 
     
     
       26. A method according to  claim 25  wherein said antibody specific for the IL-2 receptor is an antibody specific for CD25. 
     
     
       27. A method according to  claim 22 , wherein said cancer targeting molecule is an antibody. 
     
     
       28. A method according to  claim 27  wherein said antibody is a murine, chimeric, humanized, or human form of murine antibody TNT-1, TNT-2, TNT-3 or NHS76. 
     
     
       29. A method according to  claim 22  wherein said cancer targeting molecule and LEC are covalently linked. 
     
     
       30. A method according to  claim 29  wherein said cancer targeting molecule is a protein linked to LEC by genetic fusion. 
     
     
       31. A method according to  claim 30  wherein LEC is fused at its C-terminus to the N-terminus of said cancer targeting molecule. 
     
     
       32. A method according to  claim 31  wherein the cancer targeting molecule is an antibody and wherein LEC is fused to the N-terminus of the light or heavy chain of said antibody. 
     
     
       33. A method according to  claim 22  wherein said LEC has an amino acid sequence which has at least 95% sequence identity with SEQ ID NO: 3. 
     
     
       34. A method according to  claim 22  wherein said LEC has an amino acid sequence which has at least 98% sequence identity with SEQ ID NO: 3. 
     
     
       35. A method according to  claim 22  wherein said LEC has the amino acid sequence shown in SEQ ID NO: 3. 
     
     
       36. A method of reducing the size of a tumor or inhibiting the growth of cancer cells in an individual, comprising reducing the activity of immunoregulatory T cells in the individual and administering an effective amount of a cancer therapeutic agent to said individual, said cancer therapeutic agent comprising:
 an antibody; 
 a liver-expressed chemokine (LEC) having the amino acid sequence shown in SEQ ID NO: 3; 
 wherein said antibody is linked at its N-terminus to the C-terminus of said LEC; and, 
 
       wherein said cancer therapeutic agent can target to cancer cells or tumor in vivo and said LEC functions as a chemoattractant for monocytes, lymphocytes, or polymorphonuclear leukocytes. 
     
     
       37. A method according to  claim 36  further comprising reducing the activity of immunoregulatory T cells in said individual. 
     
     
       38. A method according to  claim 37  wherein said reducing the activity of immunoregulatory T cells involves (a) removing ex vivo immunoregulatory T cells from the individual or (b) depleting or inactivating in vivo immunoregulatory T cells in the individual. 
     
     
       39. A method according to  claim 36  wherein said antibody is linked to LEC by genetic fusion. 
     
     
       40. A method according to  claim 36  wherein said antibody is specific for an intracellular antigen. 
     
     
       41. A method according to  claim 36  wherein said antibody is specific for an intranuclear antigen. 
     
     
       42. A method according to  claim 41  wherein said antibody is a murine, chimeric, humanized, or human form of murine antibody TNT-1, TNT-2, TNT-3 or NHS76. 
     
     
       43. A method according to  claim 41  wherein said antibody comprises NHS76. 
     
     
       44. A method according to  claim 43  further comprising reducing the activity of immunoregulatory T cells in said individual. 
     
     
       45. A method according to  claim 44  wherein said reducing the activity of immunoregulatory T cells is achieved using at least one antibody specific for CD25. 
     
     
       46. A method according to  claim 45  wherein said reducing the activity of immunoregulatory T cells is performed before administering said cancer therapeutic agent.